Human Molecular Genetics Advance Access published online on December 9, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn418
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NLRP7 mutations in women with diploid androgenetic and triploid moles: a proposed mechanism for mole formation
1 Departments of Human Genetics, McGill University Health Center, Montreal H3G 1A4, Canada 2 Departments of Obstetrics and Gynecology, McGill University Health Center, Montreal H3G 1A4, Canada 3 Women's Reproductive Health Laboratory, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China 4 Departments of Pathology, McGill University Health Center, Montreal H3G 1A4, Canada 5 Department of Medical Genetics, Policlinico Sant'Orsola-Malpighi-University of Bologna, Bologna, Italy 6 INSERM U 782, Endocrinologie et Génétique de la Reproduction et du Développement, 32 rue des carnets, F 92140 Clamart, France
* Correspondence to Rima Slim Montreal General Hospital Research Institute, L3-121 1650 Cedar Avenue, Montreal, P.Q. H3G 1A4 Tel.: (514) 934-1934 Ext: 44550 Fax.: (514) 934-8261 E-mail: rima.slim{at}muhc.mcgill.ca
Received August 4, 2008; Revised November 5, 2008; Accepted December 5, 2008
Hydatidiform mole (HM) is an aberrant pregnancy with abnormal embryonic development and hydropic placental villi. Common moles are sporadic, not recurrent and affect one 1 in every 1500 pregnancies in Western societies. Approximately, half of common moles are complete and mostly diploid androgenetic while the remaining are partial and mostly triploid diandric. NLRP7 has been found responsible for a recurrent form of molar pregnancies. Recently, we showed that patients with NLRP7 mutations have an impaired inflammatory response to various stimuli. To date, analyzed molar tissues from patients with NLRP7 mutations have been found diploid and biparental. In this study, we report 10 new non-synonymous variants and one stop codon found in patients and not in controls. We demonstrate the presence of different types of moles, diploid biparental, diploid androgenetic, triploid, and tetraploid conceptions, in patients with NLRP7 variants. We document in-vitro and in-vivo early embryo cleavage abnormalities in three patients. We propose a two-hit mechanism at the origin of androgenetic moles. This mechanism consists of variable degrees of early embryo cleavage abnormalities leading to chaotic mosaic aneuploidies, with haploid, diploid, triploid, and tetraploid blastomeres. Surviving embryonic cells that reach implantation are then subject to the maternal immune response. Because of the patients'impaired inflammatory response, androgenetic cells, which are complete allograft, are able to grow and proliferate. In women with normal immune system, chaotic mosaic aneuploidies may also occur during early cleavage, however, androgenetic cells would die after implantation or stay undetected, confined to a small portion of the placenta.
# The two authors contributed equally to the paper.